Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.
Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.
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DOI：
10.1038/srep16449
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发表时间：
2015-11-13
影响因子：
4.6
通讯作者：
Kitajewski J
中科院分区：
文献类型：
--
作者：
Kofler NM;Cuervo H;Uh MK;Murtomäki A;Kitajewski J
周细胞调节血管稳定性，周细胞功能障碍导致视网膜病变、中风和癌症。在这里，我们将Notch定义为血管生成过程中周细胞功能的关键调节因子。在Notch 1 +/−中;在Notch 3 −/−小鼠中，Notch 1和Notch 3的联合缺乏改变了周细胞与内皮的相互作用，并减少了视网膜血管系统的周细胞覆盖。Notch 1和Notch 3显示出协同促进适当的血管基底膜形成并有助于内皮细胞静止。因此，由于Notch缺陷导致的周细胞功能的丧失加剧了由Notch 1单倍不足引起的内皮细胞活化。Notch 1和Notch 3突变的小鼠发生动静脉畸形，并显示缺血性中风疾病CADASIL的标志。因此，Notch缺陷会损害周细胞功能并导致血管病变。
Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1+/−; Notch3−/− mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies.